Quantitative pet imaging of tissue factor expression using 18f-labled active site inhibited factor vii

Abstract

There is provided a positron-emitting 18F-labelled Factor VII for non-invasive PET imaging of tumor TF expression in humans. More specifically the invention relates to human TFPET imaging of pancreatic cancer metastasis for diagnosis, staging, treatment monitoring and especially as an imaging biomarker for predicting prognosis, progression and recurrence.

1 . A positron-emitting 18-F labelled factor VIIa (FVIIa) imaging agent for use in a diagnosis by PET imaging of a Tissue Factor expressing tumor in a human, said agent comprising native human FVIIa or a variant thereof radiolabeled with 18-F, wherein the agent is to be administered in a dose of 50-400 MBq followed by PET scanning 1-6 hours after the agent has been administered, quantification through SUVmax and/or SUVmean for thereby obtaining a PET image for the diagnosis of tumor tissue factor status for use of diagnosis, treatment monitoring of as a companion diagnostics based on target-to-background ratio or absolute uptake (SUV). 
     
     
         2 . The 18-F labelled factor VIIa (FVIIa) imaging agent for use according to  claim 1 , wherein the FVIIa is SEQ ID NO: 1 and active site inhibited factor VIIa (FVIIai) and modified in such a way that it is catalytically inactive, such as having the amino acid modification comprised of Ser344, Asp242, and His193. 
     
     
         3 . The 18-F labelled factor VIIa (FVIIa) imaging agent for use according to  claim 2 , wherein FVIIai has been labelled with N-succinimidyl 4- 18 Ffluorobenzoate (18F-SFB) to produce: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The 18-F labelled factor VIIa (FVIIa) imaging agent for use according to  claim 1  to diagnose, stage or therapy monitoring in breast, gastric, esophageal, liver, colorectal and pancreatic cancer. 
     
     
         5 . The 18-F labelled factor VIIa (FVIIa) imaging agent for use according to  claim 1  as a diagnostic companion in a cancer entity where tissue factor directed therapy has been shown to be relevant, such as in breast, gastric, esophageal, liver, colorectal and pancreatic cancer. 
     
     
         6 . T The 18-F labelled factor VIIa (FVIIa) imaging agent for use according to  claim 1 , wherein agent is to be administered in a dose of 50-400 MBq. 
     
     
         7 . T A method for generating images of tissue factor expression in a human by diagnostic imaging involving administering the imaging agent of  claim 1  to said human, and generating an image of at least a part of said body to which said imaging agent is administered. 
     
     
         8 . A method of diagnosing by PET imaging a Tissue Factor expressing tumor in a human, said method comprising:
 administering a positron-emitting 18-F labelled factor VIIa (FVIIa) imaging agent, said agent comprising native human FVIIa or a variant thereof radiolabeled with 18-F,   wherein the agent is administered in a dose of 50-400 MBq followed by PET scanning 1-6 hours after the agent has been administered, quantification through SUVmax and/or SUVmean for obtaining a PET image for the diagnosis of tumor tissue factor status.   
     
     
         9 . Method according to  claim 8 , further including the step of treatment monitoring of as a companion diagnostics based on target-to-background ratio or absolute uptake (SUV). 
     
     
         10 . Method according to  claim 8  using the FVIIa of SEQ ID NO: 1, which is active site inhibited factor VIIa (FVIIai) and modified in such a way that it is catalytically inactive, such as having the amino acid modification comprised of Ser344, Asp242, and His193. 
     
     
         11 . Method according to  claim 10 , wherein FVIIai has been labelled with N-succinimidyl 4-18Ffluorobenzoate (18F-SFB) to produce: 
       
         
           
           
               
               
           
         
       
     
     
         12 . Method according to  claim 8  to diagnose, stage or therapy monitoring in breast, gastric, esophageal, liver, colorectal and pancreatic cancer